Grp94 selective inhibitors and uses thereof

Abstract

The present technology provides compounds according to Formula I or Formula III as well as compositions including such compounds useful for the treatment of metastatic cancer and/or glaucoma.

What is claimed is: 
     
       1. A compound according to Formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt and/or solvate thereof, wherein
 X 1 , X 2 , and X 3  are each independently CH or N; 
 X 4  is N or C—R 5 ; 
 X 5  is N or C—R 6 ; 
 X 6  is N or C—R 7 ; 
 W 1  is C(R 10 )(R 11 ), O, or S; 
 R 1  is isopropyl, tert-butyl, cycloalkyl, aryl, heterocyclyl, or X 7 —R 12 ; 
 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11  are each independently H, OH, alkyl, alkoxy, aryloxy, heteroaryloxy, amino, halo, trifluoromethyl, or cyano; 
 X 7  is O, S, or NH; 
 R 12  is alkyl, cycloalkyl, aryl, or heterocyclyl; 
 Z 1  is O, S, or NH; and 
 n is 0 or 1. 
 
     
     
       2. The compound of  claim 1 , wherein the compound is of Formula Ia 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt and/or solvate thereof. 
     
     
       3. The compound of  claim 1 , wherein
 X 4  is C—R 5 ; 
 X 5  is N; and 
 X 6  is C—R 7 . 
 
     
     
       4. The compound of  claim 1 , wherein R 1  is isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 
       
         
           
           
               
               
           
         
       
       where R 13 , R 14 , R 15 , R 16  and R 17  are each independently H, alkyl, alkoxy, amino, halo, trifluoromethyl, or cyano. 
     
     
       5. The compound of  claim 1 , wherein R 12  is isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 
       
         
           
           
               
               
           
         
       
       where
 X 8  and X 9  are each independently OH, amino, SH, sulfide, sulfoxide, or sulfone; and 
 R 18 , R 19 , R 20 , R 21  and R 22  are each independently H, alkyl, alkoxy, amino, halo, trifluoromethyl, or cyano. 
 
     
     
       6. The compound of  claim 1 , wherein
 one of R 5 , R 6 , and R 7  is OH, alkyl, alkoxy, aryloxy, heteroaryloxy, amino, halo, trifluoromethyl, or cyano, and the remaining R 5 , R 6 , and R 7  are each H; 
 R 8  and R 9  are each H. 
 
     
     
       7. The compound of  claim 1 , wherein
 one of R 5 , R 6 , and R 7  is OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, amino, halo, trifluoromethyl, or cyano, and the remaining R 5 , R 6 , and R 7  are each H; 
 R 8  and R 9  are each H. 
 
     
     
       8. The compound of  claim 1 , wherein
 one of R 5 , R 6 , and R 7  is OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, NH 2 , NH-CH 3 , N(CH 3 ) 2 , halo, trifluoromethyl, or cyano, and the remaining R 5 , R 6 , and R 7  are each H; 
 R 8  and R 9  are each H. 
 
     
     
       9. The compound of  claim 1 , wherein the compound Formula I is of Formula II 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt and/or solvate thereof. 
     
     
       10. A composition comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
       11. A pharmaceutical composition for treating glaucoma, the composition comprising an effective amount of the compound of  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
       12. A method of inhibiting death of a cell exhibiting mutant myocilin, the method comprising contacting the cell with a compound of  claim 1 . 
     
     
       13. A method of treating a patient or animal suffering from glaucoma, the method comprising administration of an effective amount of a compound of  claim 1  to the patient or animal suffering from the glaucoma. 
     
     
       14. The compound of  claim 1 , wherein R 12  is 
       
         
           
           
               
               
           
         
       
       where X 8  and X 9  are each independently OH, amino, SH, sulfide, sulfoxide, or sulfone.